Diabetic neuropathic pain: a role for testosterone metabolites

Diabetic neuropathy is associated with neuropathic pain in about 50% of diabetic subjects. Clinical management of neuropathic pain is complex and so far unsatisfactory. To this aim in rats rendered diabetic by streptozotocin injection we analyzed the effects of the testosterone metabolites, dihydrotestosterone and 5α-androstane-3α,17β-diol, on nociceptive and allodynia thresholds and on molecular and functional parameters related to pain modulation in the dorsal horns of spinal cord and in the dorsal root ganglia. Furthermore, the levels of dihydrotestosterone and 5α-androstane-3α,17β-diol were analyzed in the spinal cord. Diabetes resulted in a significant decrease in dihydrotestosterone levels in the spinal cord that was reverted by dihydrotestosterone or 5α-androstane-3α,17β-diol treatments. In addition, 5α-androstane-3α,17β-diol treatment resulted in a significant increase in 5α-androstane-3α,17β-diol in the spinal cord over control values. Both steroids showed analgesic properties on diabetic neuropathic pain, affecting different pain parameters and possibly by different mechanisms of action. Indeed, dihydrotestosterone counteracted the effect of diabetes on mechanical nociceptive threshold, pre- and post-synaptic components, glutamate release, astrocyte immunoreactivity and expression of interleukin-1β, while 5α-androstane-3α,17β-diol was effective on tactile allodynia threshold, glutamate release, astrocyte immunoreactivity and the expression of substance P, toll-like receptor 4, tumor necrosis factor-α, transforming growth factor β-1, interleukin-1β and translocator protein. These results suggest that testosterone metabolites are potential agents for the treatment of diabetic neuropathic pain.